RESUMEN
The individual isomers of methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate are useful intermediates for the synthesis of S1P1 receptor agonists. Herein we describe a scalable synthesis and isolation of each of the four stereoisomers of this compound in gram quantities with >98% ee and de. The utility of this approach is demonstrated by the synthesis of ((1R,3R)-1-amino-3-(4-octylphenyl)cyclopentyl)methanol in 7 steps, 11% overall yield, and >98% ee and de.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Ciclopentanos/síntesis química , Receptores de Lisoesfingolípidos/antagonistas & inhibidores , Ácidos Carboxílicos/química , Ciclopentanos/química , Estructura Molecular , Receptores de Lisoesfingolípidos/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
COT (Tpl2 in mice) is a serine/threonine MAP3 kinase that regulates production of TNF-alpha and other pro-inflammatory cytokines such as IL-1beta via the ERK/MAP kinase pathway. As TNF-alpha and IL-1beta are clinically validated targets for therapeutic intervention in rheumatoid arthritis (RA), blocking COT provides a potential avenue for amelioration of disease. Herein we describe identification of a cellular active selective small molecule inhibitor of COT kinase.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Piridinas/síntesis química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Animales , Artritis Reumatoide/tratamiento farmacológico , Química Farmacéutica/métodos , Diseño de Fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Interleucina-1beta/metabolismo , Ligandos , Quinasas Quinasa Quinasa PAM/química , Ratones , Estructura Molecular , Proteínas Proto-Oncogénicas/química , Piridinas/farmacología , Factor de Necrosis Tumoral alfa/química , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Evaluation of hit chemotypes from high throughput screening identified a novel series of 2,4-disubstituted thieno[2,3-c]pyridines as COT kinase inhibitors. Structural modifications exploring SAR at the 2- and 4-positions resulting in inhibitors with improved enzyme potency and cellular activity are disclosed.
Asunto(s)
Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Modelos Moleculares , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Piridinas/síntesis química , Piridinas/farmacología , Tiofenos/síntesis química , Tiofenos/farmacología , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Humanos , Conformación Molecular , Estructura Molecular , Piridinas/química , Relación Estructura-Actividad , Tiofenos/químicaRESUMEN
A series of 2-aminopyrimidines was synthesized as ligands of the histamine H4 receptor (H4R). Working in part from a pyrimidine hit that was identified in an HTS campaign, SAR studies were carried out to optimize the potency, which led to compound 3, 4- tert-butyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-ylamine. We further studied this compound by systematically modifying the core pyrimidine moiety, the methylpiperazine at position 4, the NH2 at position 2, and positions 5 and 6 of the pyrimidine ring. The pyrimidine 6 position benefited the most from this optimization, especially in analogs in which the 6- tert-butyl was replaced with aromatic and secondary amine moieties. The highlight of the optimization campaign was compound 4, 4-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzonitrile, which was potent in vitro and was active as an anti-inflammatory agent in an animal model and had antinociceptive activity in a pain model, which supports the potential of H 4R antagonists in pain.
Asunto(s)
Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Receptores Histamínicos/metabolismo , Animales , Biomarcadores , Antagonistas de los Receptores Histamínicos/química , Humanos , Hiperplasia/inducido químicamente , Hiperplasia/prevención & control , Ligandos , Locomoción/efectos de los fármacos , Ratones , Estructura Molecular , Pirimidinas/química , Ratas , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
A new structural class of histamine H 4 receptor antagonists (6-14) was designed based on rotationally restricted 2,4-diaminopyrimidines. Series compounds showed potent and selective in vitro H 4 antagonism across multiple species, good CNS penetration, improved PK properties compared to reference H 4 antagonists, functional H 4 antagonism in cellular and in vivo pharmacological assays, and in vivo anti-inflammatory and antinociceptive efficacy. One compound, 10 (A-943931), combined the best features of the series in a single molecule and is an excellent tool compound to probe H 4 pharmacology. It is a potent H 4 antagonist in functional assays across species (FLIPR Ca (2+) flux, K b < 5.7 nM), has high (>190x) selectivity for H 4, and combines good PK in rats and mice (t 1/2 of 2.6 and 1.6 h, oral bioavailability of 37% and 90%) with anti-inflammatory activity (ED 50 = 37 micromol/kg, mouse) and efficacy in pain models (thermal hyperalgesia, ED 50 = 72 micromol/kg, rat).